This invention relates to hypodermic needles, and more particularly to microneedles and fabrication methods thereof.
Hypodermic needles are widely used in the biomedical field for injection into and extraction from living tissue. Hypodermic needles generally have a relatively large diameter, for example on the order of millimeters. Unfortunately, the large diameter can damage biological tissue during penetration. Moreover, tissue penetration often is painful due to the relatively large needle diameter.
Accordingly, microneedles are being developed, that can have diameters that are on the order of microns. The smaller diameter needle can reduce damage to living tissue and/or reduce pain. More precise injection and extraction also may be provided. In order to inject or extract a requisite amount of liquid through a microneedle of relatively small diameter, an array of microneedles, often referred to as a microneedle array, generally is provided. For example, a microneedle array may have dimensions on the order of 1 cm2 and may include tens, hundreds or even thousands of microneedles thereon. Microneedles are described in U.S. Pat. No. 5,457,041 to Ginaven et al. entitled Needle Array and Method of Introducing Biological Substances Into Living Cells Using the Needle Array; U.S. Pat. No. 5,658,515 to Lee et al. entitled Polymer Micromold and Fabrication Process; U.S. Pat. No. 5,591,139 to Lin et al. entitled IC-Processed Microneedles; and U.S. Pat. No. 5,928,207 to Pisano et al. entitled Microneedle With Isotropically Etched Tip, and Method of Fabricating Such a Device.
Microneedles may be fabricated using micromachining or other processes that are used to form microelectromechanical systems (MEMS). These fabrication steps may be similar to those that are used for fabricating integrated circuit microelectronic devices and thereby may be capable of relatively low-cost fabrication in large numbers. Unfortunately, notwithstanding the applicability of microelectronic fabrication techniques to the fabrication of microneedle arrays, there continues to be a need to provide improved fabrication processes for microneedle arrays that can produce microneedle arrays at very low cost, for example, less than one dollar per microneedle array and preferably less than one cent per microneedle array.
The present invention provides methods of fabricating microneedle arrays by providing a sacrificial mold including a substrate and an array of posts, preferably solid posts, projecting therefrom. A first material is coated on the sacrificial mold including on the substrate and on the array of posts. The sacrificial mold is removed to provide an array of hollow tubes projecting from a base. The outer surfaces, and preferably the inner surfaces, of the array of hollow tubes are coated with a second material to create the array of microneedles projecting from the base. By using a sacrificial molding technique, low cost fabrication of microneedles may be obtained. Moreover, the sacrificial mold may be fabricated from plastic and/or metal, and need not be fabricated from a relatively expensive silicon semiconductor wafer. Low cost microneedle arrays thereby may be provided.
The sacrificial mold may be fabricated by fabricating a master mold, including an array of channels that extend into the master mold from a face thereof. A third material is molded into the channels and on the face of the master mold, to create the sacrificial mold. The sacrificial mold then is separated from the master mold. Alternatively, wire bonding that is widely used in the fabrication of microelectronic devices, may be used to wire bond an array of wires to a substrate to create the sacrificial mold.
The first material preferably is coated on the sacrificial mold by plating. When the sacrificial mold is not conductive, a plating base preferably is formed on the sacrificial mold including on the substrate and on the array of posts prior to plating. The inner and outer surfaces of the array of hollow tubes preferably are coated with a second material by overplating the second material on the inner and outer surfaces of the array of hollow tubes. The plating base preferably comprises at least one of copper and gold, including alloys thereof. The first material preferably comprises at least one of nickel and chromium, including alloys thereof. The second material preferably comprises at least one of gold, rhodium, platinum and ruthenium, including alloys thereof.
When coating the first material on the sacrificial mold including on the substrate and on the array of posts, the tips of the array of posts preferably are left uncoated so that open tubes later result. Alternatively, the tips may be removed to provide the array of hollow tubes. Moreover, the tips of the array of hollow tubes may be sharpened, for example by etching the tips. The first material may be coated on the array of posts including an obliquely extending portion of the tips. Thus, an obliquely angled tip may be formed which can increase the ability to penetrate living tissue without clogging.
First and second preferred embodiments for fabricating microneedle arrays according to the present invention now will be described. The first embodiment uses a soluble mold, whereas the second embodiment uses an array of wires projecting from a substrate.
In particular, according to the first preferred embodiments, a soluble mold is provided including a substrate and an array of posts, preferably solid posts, projecting therefrom. A plating base is formed on the soluble mold including on the substrate and on the array of posts. A plated first material is formed on the plating base except for across the tips of the array of posts. The soluble mold then is at least partially dissolved and thereby removed, to provide an array of hollow tubes projecting from a base. In order to provide the array of hollow tubes, the tips of the tubes may be removed in a separate operation. The plating base preferably also is at least partially dissolved and removed along with the soluble mold. The inner and outer surfaces of the array of hollow tubes preferably are overplated with a second material, to create the array of microneedles projecting from the base. The tips of the array of hollow tubes may be sharpened, preferably by etching the tips.
The soluble mold preferably is fabricated by fabricating the master mold including an array of channels that extend into the master mold from a face thereof. A soluble material then is molded into the channels and on the face of the master mold, to create the soluble mold. Conventional molding processes, such as injection molding, embossing, casting and/or sheet forming may be used. The soluble mold then is separated from the master mold.
When plating and/or overplating the microneedle array, the tips of the array preferably are masked to prevent plating of the tips across the entrance of the tube. Masking may be accomplished by masking the tips of the soluble mold to prevent formation of the plating base on the tips. Alternatively, the tips of the plating base may be masked to prevent further plating thereon. When masking, the tips preferably are masked at an oblique angle, to thereby allow plating of an obliquely extending portion of the tips, and thereby create angled needle points that can have reduced susceptibility to clogging.
In second preferred embodiments of the invention, a sacrificial mold is provided including a substrate and an array of wires projecting therefrom. A plated first material is formed on the sacrificial mold including on the substrate and on the array of wires except for across the tips of the wires. The sacrificial mold is removed to provide an array of hollow tubes projecting from a base. In order to provide the array of hollow tubes, the tips of the tubes may be removed in a separate operation. The inner and outer surfaces of the array of hollow tubes are overplated with a second material, to create the array of microneedles projecting from the base. In a preferred embodiment, the steps of wire bonding, plating, removing and overplating are performed in a continuous process followed by singulating individual arrays of microneedles.
The sacrificial mold preferably is provided by wire bonding an array of wires to a substrate to create the sacrificial mold. Wire bonding may be performed by wire bonding both ends of a plurality of wires to the substrate, to create a plurality of loops of wires on the substrate. The loops of wires then may be cut, or the centers of the loops may be masked to prevent plating, to create the sacrificial mold. Sharpening and oblique angle tip masking also preferably are performed, as was described above.
Microneedle arrays according to the present invention preferably comprise a monolithic core including a substrate having an array of holes therein and an array of hollow tubes that project from the substrate, a respective one of which surrounds a respective one of the array of holes. An overlayer also is provided on the monolithic core, on the outer surfaces of the array of hollow tubes, on the tips of the array of hollow tubes, and preferably on the inner surfaces of the array of hollow tubes.
The monolithic core also may comprise an array of shoulders that surround the array of hollow tubes adjacent the substrate. The shoulders may arise from the wire bonding region between the wires and the substrate of the sacrificial mold. The array of hollow tubes also may have scalloped outer surfaces. The scalloped outer surfaces may be caused by deep reactive ion etching which may be used to form the master mold.
The array of hollow tubes preferably includes sharp ends that more preferably extend at an oblique angle relative to the substrate. The monolithic core preferably comprises at least one of nickel and chromium including alloys thereof, most preferably nickel including alloys thereof. The overlayer preferably comprises at least one of gold, rhodium, platinum and ruthenium, and alloys thereof, and most preferably gold or alloys thereof. Microneedle arrays may be provided thereby.